Combinations of Tie-2 Activators and Prostaglandins and Uses Thereof

Abstract

Described herein are combinations of compounds effective for activation of Tie-2 and inhibition of HPTPβ with a compound that causes agonism of a prostaglandin receptor. The methods and compositions of the invention can be used for the treatment of glaucoma, elevated intraocular pressure, ocular hypertension, and associated conditions by, for example, reduction of intraocular pressure in the eye.

1 . A method of reducing intraocular pressure in a subject in need thereof, the method comprising:
 administering to the subject a therapeutically-effective amount of a Tie-2 activator; and   administering to the subject a therapeutically-effective amount of a compound that causes agonism of a prostaglandin receptor, wherein the Tie-2 activator is not an angiopoietin.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the administering of the Tie-2 activator and the administering of the compound that causes agonism of the prostaglandin receptor are at least 5 minutes apart. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 1 , wherein the administering of the Tie-2 activator is topical. 
     
     
         6 . The method of  claim 1 , wherein the administering of the Tie-2 activator is once daily. 
     
     
         7 . The method of  claim 1 , wherein the administering of the Tie-2 activator is twice daily. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein the therapeutically-effective amount of the Tie-2 activator is from about 0.1 mg to about 100 mg. 
     
     
         11 . The method of  claim 1 , wherein the therapeutically-effective amount of the Tie-2 activator is about 1 mg to about 5 mg. 
     
     
         12 . (canceled) 
     
     
         13 . The method of  claim 1 , wherein the Tie-2 activator is present in a composition at a concentration of from about 0.1 mg/mL to about 100 mg/mL. 
     
     
         14 . The method of  claim 1 , wherein the Tie-2 activator is present in a composition at a concentration of about 40 mg/mL. 
     
     
         15 . The method of  claim 1 , wherein the administering of the compound that causes agonism of the prostaglandin receptor is topical. 
     
     
         16 . The method of  claim 1 , wherein the administering of the compound that causes agonism of the prostaglandin receptor is once daily. 
     
     
         17 - 18 . (canceled) 
     
     
         19 . The method of  claim 1 , wherein the compound that causes agonism of the prostaglandin receptor is present in a formulation at a concentration of about 50 μg/mL. 
     
     
         20 - 25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the compound that causes agonism of the prostaglandin receptor is latanoprost. 
     
     
         27 - 45 . (canceled) 
     
     
         46 . The method of  claim 1 , wherein the administering of the Tie-2 activator and administering of the compound that causes agonism of the prostaglandin receptor treats a condition in the subject. 
     
     
         47 . The method of  claim 46 , wherein the condition is an ocular condition. 
     
     
         48 . The method of  claim 47 , wherein the ocular condition is elevated intraocular pressure. 
     
     
         49 . The method of  claim 47 , wherein the ocular condition is ocular hypertension. 
     
     
         50 . The method of  claim 47 , wherein the ocular condition is glaucoma. 
     
     
         51 . The method of  claim 1 , wherein the Tie-2 activator is a compound of the formula: 
       
         
           
           
               
               
           
         
       
       wherein: 
       Aryl 1  is an aryl group which is substituted or unsubstituted; Aryl 2  is an aryl group which is substituted or unsubstituted; X is alkylene, alkenylene, alkynylene, an ether linkage, an amine linkage, an amide linkage, an ester linkage, a thioether linkage, a carbamate linkage, a carbonate linkage, a sulfone linkage, any of which is substituted or unsubstituted, or a chemical bond; and Y is H, aryl, heteroaryl, NH(aryl), NH(heteroaryl), NHSO 2 R g , or NHCOR g , any of which is substituted or unsubstituted, or 
       
         
           
           
               
               
           
         
       
       wherein:
 L 2  is alkylene, alkenylene, or alkynylene, any of which is substituted or unsubstituted, or together with the nitrogen atom to which L 2  is bound forms an amide linkage, a carbamate linkage, or a sulfonamide linkage, or a chemical bond, or together with any of R a , R b , R c , and R d  forms a ring that is substituted or unsubstituted; 
 R a  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R b , R c , and R d  forms a ring that is substituted or unsubstituted; 
 R b  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, or together with any of L 2 , R a , R c , and R d  forms a ring that is substituted or unsubstituted; 
 R c  is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R d  forms a ring that is substituted or unsubstituted; 
 R d  is H or alkyl which is substituted or unsubstituted, or together with any of L 2 , R a , R b , and R C  forms a ring that is substituted or unsubstituted; and 
 R g  is H, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted, 
 
       or a pharmaceutically-acceptable salt thereof. 
     
     
         52 . The method of  claim 51 , wherein:
 Aryl 1  is substituted or unsubstituted phenyl;   Aryl 2  is substituted or unsubstituted heteroaryl; and   X is alkylene.   
     
     
         53 . The method of  claim 51 , wherein Aryl 2  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R e  is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and 
 R f  is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. 
 
     
     
         54 . (canceled) 
     
     
         55 . The method of  claim 1 , wherein the Tie-2 activator is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof. 
     
     
         56 . The method of  claim 1 , wherein the Tie-2 activator is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof. 
     
     
         57 . The method of  claim 51 , wherein Aryl 2  is: 
       
         
           
           
               
               
           
         
       
       wherein:
 R e  is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted; and 
 R f  is H, OH, F, Cl, Br, I, CN, alkyl, alkenyl, alkynyl, an alkoxy group, an ether group, a carboxylic acid group, a carboxaldehyde group, an ester group, an amine group, an amide group, a carbonate group, a carbamate group, a thioether group, a thioester group, a thioacid group, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, or heteroarylalkyl, any of which is substituted or unsubstituted. 
 
     
     
         58 . (canceled) 
     
     
         59 . The method of  claim 1 , wherein the Tie-2 activator is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof. 
     
     
         60 . The method of  claim 1 , wherein the Tie-2 activator is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof. 
     
     
         61 . A method of reducing intraocular pressure in a subject in need thereof, the method comprising:
 administering to an eye of the subject a therapeutically-effective amount of a Tie-2 activator of the formula:   
       
         
           
           
               
               
           
         
       
       or a pharmaceutically-acceptable salt thereof; and
 administering to the eye of the subject a therapeutically-effective amount of latanoprost, 
 
       wherein the Tie-2 activator is administered as part of a composition at a concentration of about 40 mg/mL, 
       wherein the Tie-2 activator is topically administered to the eye of the subject, 
       wherein the Tie-2 activator is administered once daily, 
       wherein the latanoprost is administered as part of a formulation having a concentration of about 50 μg/mL, 
       wherein the latanoprost is topically administered to the eye of the subject, 
       wherein the latanoprost is administered once daily, and 
       wherein the administering of the Tie-2 activator and the administering of the latanoprost reduces intraocular pressure in the subject by about 1 mmHg to about 5 mmHg. 
     
     
         62 - 74 . (canceled)